Cushing syndrome (CS), a fatal disease, is suspected in many thousands of patients each year, but confirmed in only a fraction of these. This project seeks to identify accurately which patients have Cushing syndrome, to define the etiology of their disease and to treat it optimally. A major initiative in the past year has been to evaluate the utility of plasma cortisol measurements to discriminate between pseudo-Cushing's syndrome and Cushing's syndrome. 260 patients (240 with Cushing's syndrome and 23 with pseudo-Cushing's syndrome) were studied. Using a criterion of serum cortisol of 7.5 ug/dL or more at midnight, 96% patients with Cushing's syndrome and no normal individuals or those with pseudo-Cushing's syndrome were detected. This sensitivity was superior to that obtained for any other outcome measure, including UFC, 17OHCS, any other individual cortisol value, the morning or the evening cortisol mean and the ration of morning to evening values. We also extended our previous evaluation of the Dexamethasone-CRH Test for the identification of patients with Cushing's syndrome. A cortisol of > 1.4 ug/dL at 15 minutes after CRH administration identified all patients with Cushing's disease and excluded all normal volunteers in our comparison study, suggesting that the test may be useful in patients without hypercortisolism who are suspected of having intermittent glucocorticoid excess and Cushing's syndrome. Another study compared the sensitivity of bilateral internal jugular vein (IJV) sampling with the sensitivity of bilateral inferior petrosal sinus (IPS) sampling to discriminate patients with Cushing's disease from those with ectopic adrenocorticotrophic hormone (ACTH) syndrome. Jugular vein samples were positive (central-to-peripheral ACTH ratio >2 before or >3 after CRH) in 18 of 20 patients with surgically proven Cushing's disease (sensitivity of 90%). Petrosal sinus sampling was positive in 19 of these patients (sensitivity 95%). Petrosal sinus sampling correctly lateralized the adenoma in 65%, compared to a 40% correct lateralization by IJV sampling. Both IJV and IPS samples were negative before and after CRH stimulation in the four patients with ectopic ACTH syndrome. This suggests that IJV sampling, which is a technically easier procedure, may be an excellent alternative to IPS for centers without technical expertise in IPS.